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Information for clinicians

9 Molecular genetics

Table 9.1: Molecular genetics of adult Refsum's disease

Gene symbol Chromosomal locus Protein name
PEX7 6q22-q24 Peroxisomal targeting signal 2 receptor
PHYH 10pter-p11.2 Phytanoyl-CoA dioxygenase, peroxisomal

Note: Data for this table was compiled from the following standard references: Gene symbol from HUGO; chromosomal locus from OMIM; protein name from Swiss-Prot.

Table 9.2: OMIM Entries for adult Refsum's disease

OMIM reference number Description of OMIM entry


Table 9.3: Genomic databases for adult Refsum's disease

Gene symbol Entrez Gene HGMD GeneCards GDB GenAtlas
PEX7 601757 6155803 PEX7 6155803 PEX7
PHYH 602026 9263423 PHYH 9263423 PHYH

9a Molecular genetic pathogenesis

Mutations in PHYH and PEX7 are known to cause adult Refsum's disease by interfering with the alpha-oxidation of phytanic acid.

(Section 6 - Biochemistry - gives more information on alpha-oxidation of phytanic acid.)


9b(i) Normal allelic variants

Jansen et al (2004) have described one sequence variant (c.636A>G) with an incidence of around 10% in 93 control individuals, which causes no amino acid change.

9b(ii) Pathogenic allelic variants

Sequence analysis of the PHYH gene has now been performed in 60 unrelated families and has revealed 31 different variants of which 13 (41.9%) are unique to one patient or family. (Click here to review table of results (Table 9.4).) Of these 31 variants:

9b(iii) Abnormal gene product

The impact of any mutation in the phytanoyl-CoA hydroxylase gene can be assessed by evaluating the consequences of certain mutations on the stability and the catalytic activity of the hydroxylase upon expression. Interestingly, 15 of the 17 missense mutations identified in the phytanoyl-CoA hydroxylase are located in exon 6 and 7. Structure function analysis has demonstrated that these exons code in part for the conserved beta-barrel core, which suggests that this structurally important element in the protein is susceptible to changes that directly cause loss of enzymatic activity. Click here for diagram of crystal structures.

The effect of only very few of the missense mutations has been tested by expressing the mutant proteins and testing protein stability and enzyme activity. Mukherji et al (2001) have studied a few mutants including the p.H175R, p.Q176K, and p.D177G mutants. The amino acid triad 175-177 (HQD) forms the iron binding motif and mutations in any of these amino acids have been shown to cause a fully dysfunctional enzyme since the hydroxylase is completely dependent upon Fe2+ for the conversion of phytanoyl-CoA to 2-hydroxyphytanoyl-CoA. Click here for diagrams of mutations related to the enzyme active site.

Two missense mutations, including p.G204S and p.N269H cause the peculiar effect of uncoupling the hydroxylation of phytanoyl-CoA from the conversion of 2-oxoglutarate into succinate and CO2. As demonstrated in expression studies, Mukherji et al (2001) found that no phytanoyl-CoA was hydroxylated while decarboxylation of 2-oxoglutarate to succinate and CO2 still took place, although at a much-reduced rate. This uncoupling is also observed in case of the p.Q176K substitution, which is also associated with a change in the iron binding motif.

9c PEX7

9c(i) Pathogenic allelic variants

So far, three individuals have been identified with mild mutations in the PEX7 gene.

9c(ii) Abnormal gene product

The abnormal protein results in partially impaired import of peroxisomal proteins including phytanoyl-CoA hydroxylase (see Braverman et al 2002, van den Brink et al 2003b).

Next: Literature cited

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Page last updated 26 June 2006